Skip to main content
SpringerLink
Log in

CTRP3 Activates the AMPK/SIRT1-PGC-1α Pathway to Protect Mitochondrial Biogenesis and Functions in Cerebral Ischemic Stroke

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

C1q/tumor necrosis factor-related protein-3 (CTRP3) had shown its angiogenesis and enhancement of mitochondrial biogenesis properties in the treatment of myocardial infarction, but its potential roles in cerebral ischemic stroke had not been fully understood. This study aimed to clarify the underlying mechanism of how CTRP3 regulated mitochondrial functions in hippocampal neuronal cells (HPPNCs) after oxygen-glucose deprivation (OGD)/reoxygenation (R) treatment. Results showed that impeded CTRP3 expression and weakened viability were detected in OGD/R treated HPPNCs. CTRP3 showed its ability to enhance the viability and inhibited apoptosis of HPPNCs after OGD/R treatment and it could also promote the mitochondrial biogenesis and physiological functions. Silencing of PGC-1α partially abolished the protective function of CTRP3 on mitochondria and CTRP3 mediated the expression of PGC-1α via the AMPK/SIRT1-PGC-1α pathway. These findings provided information that CTRP3 prevented mitochondria from OGD/R injury through activating the AMPK/SIRT1-PGC-1α pathway. Our study suggested that CTRP3 might have the potential to become an emerging protective agent applied in the reperfusion treatment of ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The datasets used during the present study are available from the corresponding author upon reasonable request.

Abbreviations

CTRP3:

C1q/tumour necrosis factor-related protein-3

OGD/R:

Oxygen-glucose deprivation/reoxygenation

HPPNCs:

Hippocampal neuronal cells

PGC-1α:

Peroxisome proliferator-activated receptor γ coactivator-1α

ATP:

Adenosine triphosphate

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

rtPA:

Recombinant tissue plasminogen activator

NRF:

Nuclear respiratory factors

TFAM:

Gene encoding transcription factor A

SIRT1:

Sirtuin 1

AMPK:

AMP-activated protein kinase

CTRP3:

C1q/tumor necrosis factor-related protein 3

References

  1. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, Barker-Collo S, Moran AE, Sacco RL, Truelsen T, Davis S, Pandian JD, Naghavi M, Forouzanfar MH, Nguyen G, Johnson CO, Vos T, Meretoja A, Murray CJ, Roth GA (2015) Update on the global burden of ischemic and hemorrhagic stroke in 1990–2013: tthe GBD 2013 study. Neuroepidemiology 45(3):161–176. https://doi.org/10.1159/000441085

    Article  PubMed  Google Scholar 

  2. Shi L, Rocha M, Leak RK, Zhao J, Bhatia TN, Mu H, Wei Z, Yu F, Weiner SL, Ma F (2018) A new era for stroke therapy: integrating neurovascular protection with optimal reperfusion. 38(12):2073–2091. https://doi.org/10.1177/0271678x18798162

    Article  CAS  Google Scholar 

  3. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67(2):181–198. doi:https://doi.org/10.1016/j.neuron.2010.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Becker BF (1993) Towards the physiological function of uric acid. Free Radic Biol Med 14(6):615–631. doi:https://doi.org/10.1016/0891-5849(93)90143-i

    Article  CAS  PubMed  Google Scholar 

  5. Shekhar S, Cunningham MW, Pabbidi MR, Wang S, Booz GW, Fan F (2018) Targeting vascular inflammation in ischemic stroke: recent developments on novel immunomodulatory approaches. Eur J Pharmacol 833:531–544. https://doi.org/10.1016/j.ejphar.2018.06.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zou Y, Hu J, Huang W, Ye S, Han F, Du J, Shao M, Guo R, Lin J, Zhao Y, Xiong Y, Wang X (2020) Non-mitogenic fibroblast growth factor 1 enhanced angiogenesis following ischemic stroke by regulating the sphingosine-1-phosphate 1 pathway. Front Pharmacol 11:59. https://doi.org/10.3389/fphar.2020.00059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang JL, Mukda S, Chen SD (2018) Diverse roles of mitochondria in ischemic stroke. Redox Biol 16:263–275. doi:https://doi.org/10.1016/j.redox.2018.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Niizuma K, Yoshioka H, Chen H, Kim GS, Jung JE, Katsu M, Okami N, Chan PH (2010) Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta 1802(1):92–99. doi:https://doi.org/10.1016/j.bbadis.2009.09.002

    Article  CAS  PubMed  Google Scholar 

  9. Ham PB 3, Raju R (2017) Mitochondrial function in hypoxic ischemic injury and influence of aging. Progress Neurobiol 157:92–116. https://doi.org/10.1016/j.pneurobio.2016.06.006

    Article  CAS  Google Scholar 

  10. Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, Medeiros DM, Valencik ML, McDonald JA, Kelly DP (2004) Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res 94(4):525–533. https://doi.org/10.1161/01.res.0000117088.36577.eb

    Article  CAS  PubMed  Google Scholar 

  11. Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88(2):611–638. https://doi.org/10.1152/physrev.00025.2007

    Article  CAS  PubMed  Google Scholar 

  12. Chuang YC, Chen SD (2019) Sirtuin 1 regulates mitochondrial biogenesis and provides an endogenous neuroprotective mechanism against seizure-induced neuronal cell death in the hippocampus following status epilepticus. Int J Mol Sci. https://doi.org/10.3390/ijms20143588

    Article  PubMed  PubMed Central  Google Scholar 

  13. Huang B, Cheng X, Wang D, Peng M, Xue Z, Da Y, Zhang N, Yao Z, Li M, Xu A, Zhang R (2014) Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling. Oncotarget 5(13):4732–4745. doi:https://doi.org/10.18632/oncotarget.1963

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lin JY, Kuo WW, Baskaran R, Kuo CH, Chen YA, Chen WS, Ho TJ, Day CH, Mahalakshmi B, Huang CY (2020) Swimming exercise stimulates IGF1/PI3K/Akt and AMPK/SIRT1/PGC1α survival signaling to suppress apoptosis and inflammation in aging hippocampus. Aging 12(8):6852–6864. doi:https://doi.org/10.18632/aging.103046

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huang J, Liu W, Doycheva DM, Gamdzyk M, Lu W, Tang J, Zhang JH (2019) Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE. Free Radic Biol Med 141:322–337. doi:https://doi.org/10.1016/j.freeradbiomed.2019.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Y, Wright GL, Peterson JM (2017) C1q/TNF-related protein 3 (CTRP3) function and regulation. Compr Physiol 7(3):863–878. https://doi.org/10.1002/cphy.c160044

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yi W, Sun Y, Yuan Y, Lau WB, Zheng Q, Wang X, Wang Y, Shang X, Gao E, Koch WJ, Ma XL (2012) C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart. Circulation 125(25):3159–3169. doi:https://doi.org/10.1161/circulationaha.112.099937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sun B, Ding Y, Jin X, Xu S, Zhang H (2019) Long non-coding RNA H19 promotes corneal neovascularization by targeting microRNA-29c. Biosci Rep. https://doi.org/10.1042/BSR20182394

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang S, Zhou Y, Yang B, Li L, Yu S, Chen Y, Zhu J, Zhao Y (2016) C1q/tumor necrosis factor-related protein-3 attenuates brain injury after intracerebral hemorrhage via AMPK-dependent pathway in rat. Front Cell Neurosci 10:237. https://doi.org/10.3389/fncel.2016.00237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang LH, Xu YC, Zhang W (2020) Neuroprotective effect of CTRP3 overexpression against sevoflurane anesthesia-induced cognitive dysfunction in aged rats through activating AMPK/SIRT1 and PI3K/AKT signaling pathways. Eur Rev Med Pharmacol Sci 24(9):5091–5100. doi:https://doi.org/10.26355/eurrev_202005_21202

    Article  PubMed  Google Scholar 

  21. Meng J, Wang DM, Luo LL (2019) CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling. Biomed Pharmacother [Biomedecine pharmacotherapie] 120:109489. https://doi.org/10.1016/j.biopha.2019.109489

    Article  CAS  Google Scholar 

  22. Zhang CL, Feng H, Li L, Wang JY, Wu D, Hao YT, Wang Z, Zhang Y (1861) Wu LL (2017) globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes through AMPK/PGC-1α pathway. Biochim Biophys Acta Gen Subj 1:3085–3094. https://doi.org/10.1016/j.bbagen.2016.10.022

    Article  CAS  Google Scholar 

  23. Krämer CE, Wiechert W, Kohlheyer D (2016) Time-resolved, single-cell analysis of induced and programmed cell death via non-invasive propidium iodide and counterstain perfusion. Sci Rep 6:32104. https://doi.org/10.1038/srep32104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Venegas V, Halberg MC (2012) Measurement of mitochondrial DNA copy number. Methods Mol Biol (Clifton, NJ) 837:327–335. https://doi.org/10.1007/978-1-61779-504-6_22

    Article  CAS  Google Scholar 

  25. Gill T, Levine AD (2013) Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction. J Biol Chem 288(36):26246–26255. doi:https://doi.org/10.1074/jbc.M113.476895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dickinson BC, Chang CJ (2008) A targetable fluorescent probe for imaging hydrogen peroxide in the mitochondria of living cells. J Am Chem Soc 130(30):9638–9639. doi:https://doi.org/10.1021/ja802355u

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397. https://doi.org/10.1016/s0166-2236(99)01401-0

    Article  CAS  PubMed  Google Scholar 

  28. Juurlink BH, Hertz L (1993) Ischemia-induced death of astrocytes and neurons in primary culture: pitfalls in quantifying neuronal cell death. Brain Res Dev Brain Res 71(2):239–246. https://doi.org/10.1016/0165-3806(93)90175-a

    Article  CAS  PubMed  Google Scholar 

  29. Wang G, Wang T, Hu Y, Wang J, Wang Y, Zhang Y, Li F, Liu W, Sun Y, Yu B, Kou J (2020) NMMHC IIA triggers neuronal autophagic cell death by promoting F-actin-dependent ATG9A trafficking in cerebral ischemia/reperfusion. Cell death Dis 11(6):428. https://doi.org/10.1038/s41419-020-2639-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou X, Wang HY, Wu B, Cheng CY, Xiao W, Wang ZZ, Yang YY, Li P, Yang H (2017) Ginkgolide K attenuates neuronal injury after ischemic stroke by inhibiting mitochondrial fission and GSK-3β-dependent increases in mitochondrial membrane permeability. Oncotarget 8(27):44682–44693. doi:https://doi.org/10.18632/oncotarget.17967

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wei WY, Ma ZG, Zhang N, Xu SC, Yuan YP, Zeng XF, Tang QZ (2018) Overexpression of CTRP3 protects against sepsis-induced myocardial dysfunction in mice. Mol Cell Endocrinol 476:27–36. https://doi.org/10.1016/j.mce.2018.04.006

    Article  CAS  PubMed  Google Scholar 

  32. Hou M, Liu J, Liu F, Liu K, Yu B (2014) C1q tumor necrosis factor-related protein-3 protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis through the phosphoinositide 3-kinase/Akt pathway. Int J Mol Med 33(1):97–104. doi:https://doi.org/10.3892/ijmm.2013.1550

    Article  CAS  PubMed  Google Scholar 

  33. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC (2018) Neuronal cell death. Physiol Rev 98(2):813–880. https://doi.org/10.1152/physrev.00011.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cerebral Blood Flow Metab 21(1):2–14. https://doi.org/10.1097/00004647-200101000-00002

    Article  CAS  Google Scholar 

  35. Ye Q, Chen C, Si E, Cai Y, Wang J, Huang W, Li D, Wang Y, Chen X (2017) Mitochondrial effects of PGC-1alpha silencing in MPP(+) treated human SH-SY5Y neuroblastoma cells. Front Mol Neurosci 10:164. https://doi.org/10.3389/fnmol.2017.00164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Koh JH, Hancock CR, Terada S, Higashida K, Holloszy JO, Han DH (2017) PPARβ is essential for maintaining normal levels of PGC-1α and mitochondria and for the increase in muscle mitochondria induced by exercise. Cell Metabol 25(5):1176-1185.e1175. https://doi.org/10.1016/j.cmet.2017.04.029

    Article  CAS  Google Scholar 

  37. Feng H, Wang JY, Zheng M, Zhang CL, An YM, Li L, Wu LL (2016) CTRP3 promotes energy production by inducing mitochondrial ROS and up-expression of PGC-1α in vascular smooth muscle cells. Exp Cell Res 341(2):177–186. https://doi.org/10.1016/j.yexcr.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  38. Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19(2):121–135. https://doi.org/10.1038/nrm.2017.95

    Article  CAS  PubMed  Google Scholar 

  39. Quan N, Wang L, Chen X, Luckett C, Cates C, Rousselle T, Zheng Y, Li J (2018) Sestrin2 prevents age-related intolerance to post myocardial infarction via AMPK/PGC-1α pathway. J Mol Cell Cardiol 115:170–178. doi:https://doi.org/10.1016/j.yjmcc.2018.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guo X, Jiang Q, Tuccitto A, Chan D, Alqawlaq S, Won GJ, Sivak JM (2018) The AMPK-PGC-1α signaling axis regulates the astrocyte glutathione system to protect against oxidative and metabolic injury. Neurobiol Dis 113:59–69. doi:https://doi.org/10.1016/j.nbd.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  41. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122. doi:https://doi.org/10.1016/j.cell.2006.11.013

    Article  CAS  PubMed  Google Scholar 

  42. Chandrasekaran K, Anjaneyulu M, Choi J, Kumar P, Salimian M, Ho CY, Russell JW (2019) Role of mitochondria in diabetic peripheral neuropathy: influencing the NAD(+)-dependent SIRT1-PGC-1α-TFAM pathway. Int Rev Neurobiol 145:177–209. https://doi.org/10.1016/bs.irn.2019.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

No funding was received.

Author information

Authors and Affiliations

  1. Department of ICU, Linyi People’s Hospital, Wohushan Road, Lanshan District, Linyi, 276002, Shandong, China

    Jianfei Gao

  2. Specialty of Gerontology (Cardiovascular Diseases), Weifang Medical University, No. 7166, Baotongxi Street, Weicheng District, Weifang, 261000, Shandong, China

    Tingting Qian

  3. Department of Chinese Medicine Integrated Traditional Chinese Medicine and Western Medicine, 960 Hospital of PLA Joint Service Support Force, No. 25, Shifan Road, Tianqiao District, Jinan, 250031, Shandong, China

    Wei Wang

Authors
  1. Jianfei Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingting Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.G. and T.Q. performed the experiments, analyzed data and wrote the paper. W.W. conceived and designed the experiments and revised the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Wei Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, J., Qian, T. & Wang, W. CTRP3 Activates the AMPK/SIRT1-PGC-1α Pathway to Protect Mitochondrial Biogenesis and Functions in Cerebral Ischemic Stroke. Neurochem Res 45, 3045–3058 (2020). https://doi.org/10.1007/s11064-020-03152-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03152-6

Keywords

Search

Navigation